title: Founder mutation in RSPH4A identified in patients of Hispanic descent with primary ciliary dyskinesia.
abstract: Primary ciliary dyskinesia (PCD) is a rare, autosomal recessive, genetically heterogeneous disorder characterized by ciliary dysfunction resulting in chronic oto-sino-pulmonary disease, respiratory distress in term neonates, laterality (situs) defects, and bronchiectasis. Diagnosis has traditionally relied on ciliary ultrastructural abnormalities seen by electron microscopy. Mutations in radial spoke head proteins occur in PCD patients with central apparatus defects. Advances in genetic testing have been crucial in addressing the diagnostic challenge. Here, we describe a novel splice-site mutation (c.921+3_6delAAGT) in RSPH4A, which leads to a premature translation termination signal in nine subjects with PCD (seven families). Loss-of-function was confirmed with quantitative ciliary ultrastructural analysis, measurement of ciliary beat frequency and waveform, and transcript analysis. All nine individuals carrying c.921+3_6delAAGT splice-site mutation in RSPH4A were Hispanic with ancestry tracing to Puerto Rico. This mutation is a founder mutation and a common cause of PCD without situs abnormalities in patients of Puerto Rican descent.
authors.affiliation: Department of Medicine, UNC School of Medicine, Chapel Hill, North Carolina.
authors.forename: M Leigh Anne
authors.initials: ML
authors.lastname: Daniels
authors.forename: Margaret W
authors.initials: MW
authors.lastname: Leigh
authors.forename: Stephanie D
authors.initials: SD
authors.lastname: Davis
authors.forename: Michael C
authors.initials: MC
authors.lastname: Armstrong
authors.forename: Johnny L
authors.initials: JL
authors.lastname: Carson
authors.forename: Milan
authors.initials: M
authors.lastname: Hazucha
authors.forename: Sharon D
authors.initials: SD
authors.lastname: Dell
authors.forename: Maria
authors.initials: M
authors.lastname: Eriksson
authors.forename: Francis S
authors.initials: FS
authors.lastname: Collins
authors.forename: Michael R
authors.initials: MR
authors.lastname: Knowles
authors.forename: Maimoona A
authors.initials: MA
authors.lastname: Zariwala
mesh_terms: D000293:Adolescent; D000328:Adult; D000483:Alleles; D002648:Child; D002923:Cilia / Q000235:genetics / Q000648:ultrastructure; D003598:Cytoskeletal Proteins; D005260:Female; D018703:Founder Effect; D005838:Genotype; D006630:Hispanic or Latino / Q000235:genetics*; D006801:Humans; D007619:Kartagener Syndrome / Q000235:genetics*; D008297:Male; D009154:Mutation; D011506:Proteins / Q000235:genetics*; D022821:RNA Splice Sites; D055815:Young Adult
chemical_list: D003598:Cytoskeletal Proteins; D011506:Proteins; D022821:RNA Splice Sites; C000589692:RSPH4A protein, human
keywords: Kartagener syndrome; RSPH4A; cilia; sequencing